Process foe preparing



UNITED STATES PATENT OFFICE .'PROCESS FOR PREPARING 1- (DIHYDROXY- PHENYL) 2 AMINOBUTANOL-l AND IN- TERMEDIATES Chester Merle Suter and Arlo Wayne Ruddy, Al-

3 bany, N. Y., assignors, by mesne assignments,

to-Winthrop-Stearns Inc., New York, N. Y., a corporation of Delaware "No Drawing. Original No. 2,431,285, dated No- "vember 18, 1947, Serial No. 526,809, March 16,

1944. Application for reissue February 9, 1949,

Serial No. 75,483

16 Claims. 1 This invention relates to therapeutic agents "having a vasocons'trictor action, intermediates --usefu1in'the production 'there'of and to improved methods for their preparation.

Where R and R" are arylmethyl, and X is a middle halogen, i. e., chlorine or bromine, with a primary amine having the formula R-Nl-Iz, where R. is diarylmethyl, and hydrogenating the result- It'has beenfound that the compound having ing (diarylmethyD-amino ketone or an acid adthe-formula dition salt thereof in the presence of a noble 0H metal, preferably palladium, catalyst.

We prefer to conduct our new process by heat- Hoing u-bromma-dibenzylo-Xybutyrophenone with benzhydrylamine. The resulting a-bBllZhYdI'Yl- 013-013-023 a1nino-3,l-dibenzyloxybutyrophenone is convert- 5 NH? ed into an acid addition salt such as the hydrochloride, by treating the free base with the requif chemlcauy'as site amount of acid. This salt isdissolved in a sspsclally f suitable solvent such as alcohol and hydrogenated tageous propertles" whlchmake a pecuharly in the presence of a palladium catalyst. After useful vasoconstrictoragent. In particular, it is three moles of hydrogen are absorbed, t prom "equally as eifective as epinephrine in the relief of net Mama-mmBAPdihydroxybutymphenone can be acute asthmatic attacks in doses /2 larger and isnlatei on further hydrogenation, this is the relief is accompanied-by fewer side-effects. duced to l ,(3y dihydroxyphenyl) This compound is approximately only /1 m a 9 butanol. Thus the two benzyl groups and the as eplneph nnecumpound enJDys the l v benzhydryl group are removed by hydrogenolysis, and especially valuable property of exerting its While the ktone group is reduced to the desired action without exciting the central nervous syshydmxyl gmum In this connection it must be temnor raising thesystoho blood pressure. Inobserved that 1-(3,4=-dihydroxyphenyl) -2-aminostead; itlowers the diastolic blood pres and l butanol is theoretically capable of existing in increases the pulse rate; thus improving c r two racemic forms since the carbon atoms numtion without a'proportionate rise in cardiac work. bered 1 and 2 in the above fermula are both asym "These highly'desirablepmpertisare enjoyed net metric and different. It is quite surprising that only by the. compound 1-(3,4ad hydroxyp e so only one kind of racemate is formed according z'ammol'bumnol ltselfi that'ls m the form of to our new process and that this racemate is the the' free base, but" also In theform its acid one desired and having the favorable nhysi- --addition' salts. Such acidaddition salts include magical and therpeutic pmperfiesl -the hydrochloride,- the sulfate, the tartrate, and our invention also contemplates new interme 1n general all of-1ts'other salts with acids which dimes especially f l for the preparation f are themselves non-toxic to the orgarnsm 1n bwfidihydmxyphenyl) 2 amino 1 butano1 "dosages Corresponding to the therapeutic dose These intermediates are aminoketones having the the amine salt. formula We have set ourselves to the problem of devel oping a satisfactory procedure by which this drug 40 OR v-may -bemanufacturedandmada available to the medical profession. :--In searching for suitable means of obtaining this amine, the usual methods for preparing arylalkanolamines proved to be un- H satisfactory. 2

Now we have found, however, that the com 0 N53 pound or its salts can .be prepared readily and economically by reactin a compound newly diswhere R 18 a member of the class consistin of covered by us and havmg the formula hydrogen and diarylmethyl and R and R" are members of the class consisting of hydrogen and arylmethyl, and the acid addition salts of these new amino-ketones.

Our invention is further illustrated by the following example, but without being restricted b5 thereto.

EXAMPLE (a) 3,4-dihydroxybutyrophenone To 165 gm. of catechol in 660 cc. of dry chlorobenzene is added 200 gm. of n-butyryl chloride, and the mixture heated at 50 C. for 30 minutes. It is then cooled and 426 gm. of anhydrous aluminum chloride is added in small portions. Then the temperature of the mixture is gradually raised to 100 C. and held there for 3 hours. The mixture is hydrolyzed by pouring it onto ice and hydrochloric acid, and the chlorobenzene removed by steam distillation. While the mixture is still warm, 75 cc. of concentrated hydrochloric acid and 125 cc. of toluene are added. After thorough cooling, the deposited solid is collected by filtration and washed well With Water and toluene. After recrystallization from water, this product, 3,4 dihydroxybutyrophenone, melts at 146- 146.5 C.

(b) 3,4-dibenzylowybutyrophenone A mixture of 184.5 gm. of 3,4-dihydroxybutyrophenone, 278.5 gm. of benzyl chloride, 18'? gm. of anhydrous potassium carbonate, 13.5 gm. of sodium iodide in 500 cc. of alcohol and 8 cc. of water is refluxed and stirred for hours when all efiervescence has ceased. The alcohol is distilled off and any unreacted benzyl chloride removed by steam distillation. The warm mixture is poured into dilute sodium hydroxide, cooled, filtered, and washed with water until neutral to litmus. Recrystallization from alcohol gives a 90% yield of 3,4-dibenzyloxybutyrophenone, M. P. 86-8'7 C.

(c) a-Bromo-3,4-dibenzylowybutyrophenone To 335.5 gm. of 3,4-dibenzyloxybutyrophenone dissolved in 1500 cc. of methylene chloride is added 110 gm. of powdered calcium carbonate and. then 149 gm. of bromine in 400 cc. of methylene chloride. The excess calcium carbonate is dissolved with dilute hydrochloric acid, the methylene chloride layer separated, washed with water, and dried over sodium sulfate. After removing the solvent under reduced pressure, the residue is recrystallized from alcohol. A 70% yield of cream-colored crystals, M. P. IOU-101 C., is obtained.

(d) a Benzhydrylamino 3,4 dz'benzyloxybutyrophenone hydrochloride (e) 1 -(3,4dihydro:z:yphenyl) 2 amino 1- butanol hydrochloride To 28.9 gm. of a-benzhydrylamin-o-li,4-dibenzyloxybu-tyrophenone hydrochloride, dissolved in 150 cc. of absolute alcohol, is added 0.5 gm. of palladium sponge catalyst, prepared according to the method of Willstatter and Waldschmidt-Leitz (Berichte 54, 123, 1921). The mixture is shaken at 55-70 C. under fifty pounds pressure until The alcohol is completely 4 three equivalents of hydrogen have been used. After the alcohol is removed, the residue is dissolved in water and the toluene and diphenylmethane removed by extracting with ether. The aqueous solution is boneblacked and further hy-i drogenated until the fourth equivalent of hydrogen has been used. The catalyst is removed and the solution taken to dryness under reduced pressure. The residue is boneblacked in absolute alcohol, an equal volume of acetone added and then dry ether added until precipitation is complete. A yield of colorless mate-rial is obtain-ed. When completely dry it melts with decomposition at 199-200 C.

When the hydrogenation is interrupted after the absorption of three moles of hydrogen and the reaction mixture worked up at this point, by evaporating the alcohol, dissolving the residue in water, and rendering the aqueous solution a1- kaline by addition of aqueous ammonia, u-amino- (3,4 dihydroxyphenyl) butyrophenone is obtained. It melts at 187-188" (3., with decomposition, and forms a hydrochloride melting at approximately 178-179 This salt, and other acid addition salts, can be prepared by adding the requisite acid to an alcoholic suspension of the base, and isolating the salt by evaporation or by precipitation with ether.

It will be appreciated that our invention is subject to numerous variations with regard to the particular details involved in the various steps. For example, instead of using benzyl groups to protect the phenolic hydroxyl groups during halogenation, we can employ other protecting arylmethyl groups such as p-chlorobenzyl, p-methoxybenzyl, p-methylbenzyl, or the like.

Similarly, instead of using benzhydrylamine as the a,a-diarylmethylamine, we can use derivatives of benzhydrylamine in which one or both benzene rings are substituted by unreactive groups such as halogen, alkyl or alkoxyl.

However, the use of substituted benzyl, land substituted benzhydryl com-pounds usually offers no advantage, and in practice we prefer to use the cheaper, ring-unsubstituted compounds.

Likewise, instead of using a bromoketone, we can also employ the corresponding chloroketone. In the appended claims we employ the term middle halogen to include both bromine and chlorine.

The noble metal catalyst can be any metal of the platinum group. We prefer palladium because it is cheaper than platinum, and affords a clean-cut hydrogenation, in contrast to some instances where We have found the hydrogenation difficult to control, when using platinum.

Because of these permissible variations we do not limit the scope of our invention to the specific forms shown. Rather, the scope is defined by the s-ubjoined claims.

What we claim is:

1. The process which comprises reacting a compound having the formula c-on-can o' x where R and R" are arylmethyl and X is a, middle halogen, with an amine having the formula RNH2, where R is a diarylmethyl, and hydrogenating the resulting a- (diarylmethyl) -amino]- ketone or an acid addition salt thereof in the presence of a noble metal catalyst, thereby pro- C., with decomposition.v

ducing a. derivative of I-(BA-dihydroxyphentrD- Z-amlno-l-butanol, or an acid addition salt thereof.

2. A process according to claim 1 where the noble metal catalyst is palladium.

3. A process according to claim 1 where the amine of formula R'-NH2 is benzhydrylamine.

4. The process which comprises reacting abromo-3,4-dibenzyloxy-butyrophenone with benzhydrylamine, forming an acid addition salt of the resulting a-benzhydrylamino-3,4-dibenzyloxy-butyrophenone by reacting the latter with an acid, and hydrogenating the resulting acid addition salt of a-benzhydrylamino-3,4-dibenzyloxybutyrophenone in the presence of a noble metal catalyst, thereby producing an acid addition salt of 1-(3,4-di-hydroxyphenyl)-2-amino-1- butanol.

5. The process which comprises reacting a-biO- mo-3,4-dibenzyloxybutyrophenone with benzhydrylamine, forming the hydrochloride of the resulting o. benzhydrylamino 3,4 dibenzyloxybutyrophenone by reacting the latter with hydrochloric acid, and hydrogenating the resulting hydrochloride of a-benzhydrylamino-3,4-dibenzyloxybutyrophenone in the presence of a palladium catalyst, thereby producing the hydrochloride of 1- (3,4-dihydroxyphenyl) -2-amino-1-butanol.

6. In a process for producing 1-(3,4-dihydroxyphenyl) -2-amino-1-butanol and its acid addition salts, the step which comprises reacting a compound having the formula where R and R" are arylmethyl and X is a middle halogen, with an amine having the formula RNH2, where R is a diarylmethyl.

7 In a process for producing 1-(3,4-dihydroxyphenyl)-2-amino-1-butanol and its acid addition salts, the step which comprises reacting bromo-3,4-dibenzyloxybutyrophenone with benzhydrylamine.

8. In a process for producing 1-(3,4-dlhydroxyphenyD-Z-amino-lbutanol and its acid addition salts, the step which comprises hydrogenating, in the presence of a noble metal catalyst, a member of the class consisting of a compound having the formula where R and R" are arylmethyl, and R is diarylmethyl, and acid addition salts of said compound.

9. A process according to claim 8 wherein the noble metal catalyst is palladiiun.

10. In a process for producing l-(3A-dihydroxyphenyl)--2-am1no-1-butanol and its acid addition salts, the step which comprises hydrogenating a-benzhydrylamino-3,4-dibenzyloxybutyrophenone in the presence of a palladium catalyst.

11. A compound having the formula (FRI! o-on-om- NHR where R is a member of the group consisting of hydrogen and diarylmethyl and R and R" are members of the group consisting of hydrogen and arylmethyl, and the acid addition salts of said aminoketones.

12. A compound having the formula where R is diarylmethyl and R and R" are arylmethyl.

13. a Benzhydrylamino 3,4-dibenzyloxybutyrophenone, having the formula C-CH-C|H| 0 NH-benzhydryl and forming a hydrochloride melting at approximately 1'75-1'76 C., with decomposition.

14. a. Amino 3,4 dihydroxybutyrophenone, having the formula 15. An acid addition salt of a.-amino-3,4-dihydroxy-butyrophenone.

16. a-Amino-3,4-dihydroxybutyrophenone hydrochloride, melting at approximately FIB-179 C. with decomposition.

CHESTER MERLE SUTER. ARLO WAYNE RUDDY.

No references cited. 

